2-Amino-1-(2-imidazolin-2-yl)-2-imidazolines

ABSTRACT

The present invention relates to 2-amino-1-(2-imidazolin-2-yl)2-imidazolines, the free base of which has the following structural formulas:   WHEREIN R1 is hydrogen, lower alkyl, cycloaklyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic or aryloxy; R2 is hydrogen, lower alkyl, aryl and substituted aryl; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring; R3 and R4 are hydrogen, lower alkyl, aryl, or substituted aryl; R5 is hydrogen, lower alkyl, aryl or substituted aryl; N IS AN INTEGER FROM 0 TO 10. The compounds of this invention are useful as antiarrhythmic agents as well as antibacterial agents.

United States Patent [1 1 Wittekind et al.

[ Dec. 16, 1975 [54] 2-AMlNO-l-(2-IMIDAZOLIN-2-YL)-2- IMIDAZOLINES [75] Inventors: Raymond R. Wittekind, Morristown; John Shavel, Jr., Mendham, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

22 Filed: Nov. 7, 1973 21 Appl. No.: 414,561

Related U.S. Application Data [60] Division of Ser. No. 253,074, May 15, 1972, Pat. No. 3,798,232, and a continuation-in-part of Ser. No. 6,639, Jan. 28, 1970, Pat. No. 3,666,767.

[52] US. Cl. 260/309.6

[51] Int. Cl. C07D 49/34 [58] Field of Search 260/309.6, 309.2

[56] References Cited UNITED STATES PATENTS 2,987,522 6/1961 Shen 260/309.6 3,467,668 9/1969 Gruber et al. 260/309.6

3,666,767 5/1972 Wittekind et al. 260/296 R 3,798,232 3/1974 Wittekind et al. 260/309.6 3,803,157 4/1974 Wittekind et al. 260/296 R 3,806,518 4/1974 Wittekind et al. 260/309.6

Primary ExaminerEthel G. Love Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow [57] ABSTRACT The present invention relates to 2-amino-l (2- imidazolin-2-yl)-2-imidazolines, the free base of which has the following structural formulas:

1 Claim, No Drawings R is hydrogen, lower alkyl, cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, or aryloxy; I

R is hydrogen, lower alkyl, aryl, substituted aryl, or

R and R taken together with the nitrogen atom to which they are attached form a heterocyclic ring, for example, a 5- or 6-membered ring;

R and R are hydrogen, lower alkyl, aryl or substituted aryl;

R is hydrogen, lower alkyl, aryl or substituted aryl;

n is an integer from to 10. v

In the definitions for R R R R and R the term lower alkyl includes aliphatic hydrocarbons having 1 to carbon atoms in the carbon chain. It includes straight chain as well as branched chain radicals. The term also includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. The term cycloalkyl encompasses saturated monocyclic groups having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term heterocyclic encompasses the monocyclic 5- and 6-membered hetero rings having at least one hetero atom in the ring which may be either nitrogen, oxygen or sulfur. Representative heterocyclics falling within this definition are, for example, aziridinyl, azetidinyl, pyrrolyl, pyrrolidinyl, morpholino, thienyl, fury], pyridyl, piperidyl, indolyl, and the like. Additionally, these 5- and 6-membered heterocyclics may have further substituents in their ring'portions by groups such as, hydrogen, halogen, lower alkyl and lower alkoxy. The term aryl denotes a monocyclic or bicyclic hydrocarbon radical, preferably of 6 to 10 carbon atoms, such as for example, phenyl, naphthyl and the like. The term substituted aryl as used herein includes aryl as defined above in which one or more of the hydrogen atoms of the aryl portion have been substituted by groups such as, halogen, hydroxyl, lower alkyl, trifluoromethyl, amino, substituted amino or lower alkoxy. X, in the formulas below, includes anions suchas the halides, for example, fluoride, chloride, iodide, bromide, or other anions such as, sulfate, nitrate, phosphate, maleate, fumarate and the like.

The definitions for R R R R, and R and n as used hereinafter have the same meanings as defined above.

The compounds of this invention exhibit antiarrhythmic activity, for example, at a dosage of about 2 to 3 mg/kg, body weight in a mammal such as, cats, dogs, monkeys and the like. In experimentally induced arrhythmia, such as those induced by ouabain, at a dosage of 2 to 3 mg/kg, the compounds of this invention are capable of arresting such arrhythmia. Generally speaking, the compounds of this invention are useful in conditions associated with cardiac arrhythmia. A dosage level of about 1 to 10 mg, several times daily is recommended. This dosage regimen can be varied according to body weight, sex and species of the mammal being treated.

Among the dosage forms which can be used to administer these compounds are, for example, tablets, powders, elixirs, suspensions and the like. These dosage forms are formulated by procedures known to the pharmacists art.

All the compounds of this invention also exhibit antibacterial activity against gram positive cocci, such as Staphylococcus aureus or gram negative bacilli, such as E. coli. To use the compounds as anti-bacterials, they are formulated from 1 to 10% by weight with a dermatologically acceptable vehicle, such as talc, petrolatum and applied liberally to the site infected with the susceptible bacteria.

The preferred genus of thiss invention is a compound of the structure:

where R a heteroaromatic group such as furfuryl, 2-(3H- pyrazol-3-yl), 2-(4-imidazolyl), 5-methyl-l,3,4- thiadiazolyl, 2-benzimidazolyl, Z-benzthiazolyl,

3 4 2-thiaz0lyl, 2-(6-methoxypyridazinyl) 'and the like. hydroiodide 3 and triethyl[1-(2-imidazolin-2-yU-2- n to 3. imida z oliin-Z-yl-]ammonium iodide "hydroiodi'de meanionic g p such 85 halide, eate. fumarthanethiol 4 were prepared by the processes depicted ate and the like- 7 on page eight, where A has the same meaning as given These compounds are prepared as follows: above.

A. 11-(011, -NH, I

-sc11, R-(cn --NH & HA HA N4L NH NAN L l l .l

g 11(c,11,),A' Z

a -c11,s11

Nll 'llA l .l

where R, n and A have the same meaning as above. 2-Methylmercaptoimidazol-2-ine 6 and the corre- 2-Propanol and acetonitrile are useful solvents for sponding salts 5 are prepared according to procedures these processes described in S. R. Aspinall and E. J. Bianco, J. Org.

C/1em., 73, 602 1951 w. Wilson,J. C/1em.S0c., 1389 The amines 2 and their acid addition salts are avail- (1955) and A. L. Langis and F. Herr, Can. 736, 494 able from Aldrich Chemical Company and can be pre- (June 14, 1966), CA, 65, l22l2 (1966).

N N N 5011 5011, sc11 3 'HA N HA 11 11 n uu N I N Z (C=H=)3N *9 (0,11,

3 N I 1 1 1 11 N11 L l 2 i pared by methods outlined in Synthetic Organic Chem- 2- Propanol and-.acetonitrile are useful solvents for ism-y by R. B. Wagner and H. D. Zook. John Wiley and these processes. v Sons, Inc, New York, N.Y., 1953. p. 653 and p. 832. To further illustratethe practice of this invention. the

l-(2-lmidazolin-2-yl)-2-(methylthio)-2-imidazoline following examples are included:

EXAMPLE 1 2(Furfurylamino)-1-(2-imidazolin-2-yl)-2-imidazoline Hydroiodide A solution of furfurylamine (11.6 g, 0.120 mole), 1-( 2-imidazolin-2-yl Z-methylthio )-2-imidazoline hydroiodide (37.1 g, 0.120 mole) and 2-propanol (300 ml) was heated under reflux for 1 hour during which time a steady stream of nitrogen was passed through the reaction mixture. The solution was allowed to cool to room temperature and the solid was collected. Recrystallization from 2-propanol (2 times) gave 14.6 g (34%) of the imidazoline, mp. 201202.

Anal. Calcd for C H IN O: C, 36.58; H, 4.66; l, 35.14; N, 19.39; 0, 4.43. Found: C, 36.59; H, 4.44; I, 34.98; N, 19.09; 0, 4.72.

EXAMPLE 2 1-( 2-lmidazolin-2-yl )-2- [2-( 3H-pyrazol-3-yl )ethyl- ]amino -2-imidazoline Dihydrochloride A solution of 2-(3H-pyrazol-3-y1)ethylamine 1 1.0 g, 0.0600 mole), 1-( 2-irnidazolin-2-yl )-2-( methylthio)-2- imidazoline hydrate (12.1 g, 0.0600 mole) and 2- propanol (180 ml) was heated under reflux for 3 hours while a steady stream of nitrogen was passed through the medium. The reaction mixture was allowed to cool to room temperature. The precipitate was collected. Recrystallization (2 times) from absolute ethanol gave 6.55 g (34.1%) of the imidazoline, mp. 292293.

Anal. Calcd for C H C1 N C, 41.26; H, 5.98; C], 22.14; N, 30.65. Found C, 41.36; H, 6.05; Cl, 22.38; N, 30.78.

EXAMPLE 3 1-( 2-lmidazolin-2-yl )-2- [2-( 4-imidazolyl )ethyl- ]amino -2-imidazoline Hydrochloride A solution of histamine dihydrochloride (22.1 g., 0.120 mole), 1-( 2-imidazolin-2-yl )-2-( methylthio )-2- imidazoline hydrate (24.2 g., 0.120 mole) and 2- propanol (400 ml.) was heated under reflux while a steady stream of nitrogen was passed through the medium. The reaction mixture was allowed to cool to room temperature. The solid was collected and recrystallized from ethanol (3 times); yield 4.52 g. (13.2%) of the imidazoline, mp. 192.0-193.0.

Anal. Calcd. for C H ClN C, 46.54; H, 6.39; Cl, 12.49; N, 34.58. Found: C, 46.43; H, 6.24; C], 12.25; N, 34.72.

EXAMPLE 4 2- l-(2-Imidaz0lin-2-yl)-2-imidazolin-2- yl]amino benzothiazole Hydrobromide Monohydrate.

A solution of Z-aminobenzothiazole (22.5 g., 0.15 mole), l-( 2-imidazolin-2-yl )-2-( methylthio )-2- imidazoline hydroiodide (15.6 g., 0.15 mole) and acetonitrile (750 ml.) was heated under reflux for 20 hours during which time a stream of nitrogen was passed through the reaction mixture. The solution was allowed to cool to room temperature. The solid was collected and recrystallized from acetonitrilewater; yield 7.05 g. (11%) of the imidazoline, m.p. 305-307.

Anal. Calcd for C H IN OS: C, 36.13; H, 3.96; l, 29.36; N, 19.44; S, 7.42. Found: C, 35.95; H, 4.14; l, 29.43; N, 19.51; S. 7.67.

EXAMPLE 5 2- 1-( 2-lmidazolin-2-yl )-2-imidazolin-2-yl]amino -5- methyl-1 ,3 ,4-thiadiazole A solution of 2-amino-5-methyl-1,3,4-thiadiazole (8.06 g., 0.07 mole), 1-(2-imidazolin-2-yl)-2-(methylthio)-2-imidazoline hydroiodide 21.9 g. (0.07 mole) and acetonitrile (400 ml.) was heated under reflux for 3 days while a stream of nitrogen was passed through the reaction mixture. The solid was collected from the hot solution, and then dissolved in water (300 mL), basified with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. v

Recrystallization of the residue from acetone gave 1.86 g. (11%) of the imidazoline, m.p. l192.

Anal. Calcd for C H N S: C, 43.01; H, 5.21; N, 39.01; S, 12.77. Found: C, 43.05; H, 5.12; N, 39.10; S, 12.73.-

EXAMPLE 6 2- [l-(2-lmidazolin-2-yl)-2-imidazolin-2- yl]amino 'benzimidazole Hydroiodide.

A mixture of 2-aminobenzimidazole (8.0 g, 0.060 mole), triethyl[ l-( 2-imidazolin-2-yl )-2-imidazolin-2- yl]ammonium iodide hydroiodide methanethiol (32.5 g, 0.0600 mole) and 2-propano1 (distilled from calcium hydride, 150 ml) was heated under reflux, with stirring, for 23 hours. A slow stream of nitrogen was bubbled through the reaction mixture during this time. The reaction mixture was allowed to cool to room temperature. The precipitate was collected and recrystallized from methanol; yield 2.9 g (12%) of the imidazoline hydroiodide, mp. 289.5290.0 dec.

Anal. Calcd for C H N I: C, 39.31; H, 4.06; N, 24.68; I, 31.95. Found: C, 39.35; H, 4.16; N, 24.87; 1, 31.77.

EXAMPLE 7 3- [1-(2-imidazolin-2-yl)-2-imidazolin-2-yl]amino -6- methoxypyridazine Hydroiodide A solution of 3-amino-6-methoxypyridazine (48.8 g., 0.400 mole), 1-(2-imidazolin-2-yl)-2-(methylthio)-2- imidazoline hydroiodide g., 0.400 mole) and acetonitrile (3 l.) was heated under reflux for 70 hours while a stream of nitrogen was passed through the reaction medium. The reaction mixture was allowed to cool to room temperature. The precipitate was collected and recrystallized from ethanol-water; yield 14.6 g. (9.0%) of the imidazoline hydroiodide, m.p. 249250.

Anal. Cald. for C H IN O: C, 33.95; H, 4.14; l, 32.61; N, 25.19; 0, 4.11. Found: C, 33.87; H, 4.18; I, 32.87; N, 25.31; 0, 4.35.

EXAMPLE 8 2- l-( 2-lmidazolin-2-yl)-2-imidazolin-2-yl]aminothiazole Hydroiodide 

1. 1-(2-IMIDAZOLIN-2-YL)-2- (2-(4-IMIDAZOLYL)ETHYL)AMINO2-IMIDAZOLINE HYDROCHLORIDE. 